Thursday, February 23, 2012

Non-pharmacological Variables Shape the Subjective Experience of Psilocybin

Back in the early days of LSD use and research, Timothy Leary stressed the importance of "set and setting" in determining whether or not someone had a good experience on the drug. Most users acknowledge the importance of having a good mind-set and a pleasant setting when using hallucinogens.

A recent study posted in PLoS ONE wanted to test the reality of this injunction with psilocybin (for testing the traditional hallucinogens, the short half-life of psilocybin makes it the best candidate). The researchers looked "investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin." The results confirmed, at least in part, the set and setting model.

Prediction of Psilocybin Response in Healthy Volunteers

Erich Studerus1*, Alex Gamma2, Michael Kometer1, Franz X. Vollenweider1

1 Neuropsychopharmacology and Brain Imaging & Heffter Research Center, University Hospital of Psychiatry, Zurich, Switzerland  
2 Department of Clinical and Social Psychiatry, University Hospital of Psychiatry, Zurich, Switzerland


Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin.
Citation: Studerus E, Gamma A, Kometer M, Vollenweider FX. (2012). Prediction of Psilocybin Response in Healthy Volunteers. PLoS ONE 7(2): e30800. doi:10.1371/journal.pone.0030800

Here is the introduction to the paper, which introduces the central issues that led to the investigation undertaken with this project.


Responses to classical hallucinogens, such as psilocybin, strongly vary between and within subjects, even when the drug dose is kept constant [1], [2]. It has therefore long been postulated that a large proportion of inter- and intraindividual differences in reactions to hallucinogens is determined by non-pharmacological variables – also often referred to as set and setting. As originally defined by Leary et al. [3], set refers to the preparation of the subject, his personality structure, and current mood state, whereas setting refers to the the physical, social, and cultural environment in which the drug is taken. Although set and setting influence the psychological effects of any psychotropic substance, including alcohol and nicotine (e.g. see [4]), the effects of hallucinogens seem to be particularly strongly determined by these conditions [1], [5]. In fact, they are not only said to be influenced by an individual subject's mental state and surroundings, but to pharmacologically amplify the impact of these non-pharmacological factors on human experience [6], [7].

Since human hallucinogen research has been dormant for almost three decades and has only come to a revival recently [8], most of what we know today about non-pharmacological predictors of hallucinogen response is based on a small number of older studies, many of which do not conform to modern methodological standards. Nevertheless, most of these studies suggest that responses to classical hallucinogens are dependent at least to some degree on the personality structure (e.g., [9][16]). Further influencing factors include the mood state immediately before drug intake (e.g., [14], [17]), peer-support [18], estimated emotional support [3], expectations of the subjects (e.g., [3], [14], [17]), age [17], [19], body morphology [17], size of the group in which the drug is taken [3], and drug pre-experiences [3], [17].

However, most of these studies have obtained only a limited number of potential predictors at a time. Furthermore, almost all of these studies have relied on simple correlations instead of multiple regression to investigate associations between set and setting variables and drug response. Thus, they did not adjust for potentially confounding variables and also could not reveal the order of importance of different variables. The only exception is a study by Dittrich and his colleagues [14], [20], which has used multiple regression to predict responses to N,N-dimethyltryptamine (DMT), nitrous oxide, and sensory deprivation from a large number of different set and setting variables. Unfortunately, the sample size of the DMT subgroup was relatively small (n = 45), and the study so far has only been published in book chapters.

Given these methodological problems and given that a growing number of investigators are using hallucinogens for experimental and therapeutic purposes [8], new investigations on set and setting are both timely and important. Beyond basic research, such investigations could serve the following purposes. First, they can help to improve the safety of controlled experiments using hallucinogens by providing a basis for deciding which subjects to exclude at screening and how to adjust the environment and procedures for minimizing the risk of adverse reactions. Second, they help to better standardize future experiments. For instance, treatment allocation can be improved by stratifying experimental and control groups on the most important non-pharmacological predictors and efforts in controlling confounding variables can be better directed to those that really matter. Furthermore, the most important predictors can be used for covariate adjustment in randomized controlled trials, which improves precision and power in the estimation of treatment effects [21]. Last but not least, knowledge about non-pharmacological predictors can significantly advance our understanding of the neurobiological systems involved in the actions of hallucinogens. This is because individual differences in personality, demographic characteristics, mood, etc. on the one hand, and responsiveness to hallucinogens on the other hand, could be both related to structural and functional differences in specific neurotransmitter systems. In the case of psilocybin, differences are most likely related to differential functioning and density of cortical 5-HT2A receptors because this is the main site of action of classical hallucinogens [22], [23]. However, other receptors (particularly the 5-HT1, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors) and neurotransmitter systems (particularly the glutamate system), which are additionally involved in the actions of classical hallucinogens [8], [24], might also contribute to common individual differences.

Thus, to further elucidate the dependency of psilocybin response on set and setting, the present study investigates the relative importance of 24 predictor variables, including age, sex, years of education, body mass index, personality traits, drug pre-experience, mental state before drug intake, psychological distress, experimental setting, and drug dose. The analysis is based on the pooled data of 23 controlled experimental studies. Most of these have been published before as single studies. Additionally, data from eight of the 23 pooled studies (i.e., those carried out between 2000 and 2008) were used in a recent pooled analysis on acute, subacute, and long-term subjective effects of psilocybin [2] and data from 20 studies (i.e., all but the three most recent studies) were used in a recent psychometric investigation of the OAV questionnaire [25]. However, none of these studies have yet reported about the dependency of psilocybin effects on non-pharmacological predictors.

This study improves on previous predictor studies in several ways. First, the sample size (n = 409) is about four times as large as in the largest previous study [3]. Second, the predictor variables that we used covered a wide range of potentially important domains, and the effects of these predictors were adjusted for the most important confounders. Third, all outcome variables and most of the predictor variables were measured by validated instruments. Fourth, psilocybin was administered under highly standardized research conditions. Finally, by using modern statistical techniques, such as the bootstrap, more reliable estimates of variable importance were obtained.
Read the whole study.
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